The harmala alkaloid harmine is a modulator of circadian <i>Bmal1</i> transcription

Onishi, Yoshiaki; Oishi, Katsutaka; Kawano, Yasuhiro; Yamazaki, Yoshimitsu

doi:10.1042/bsr20110002

Cited by 34 publications

(40 citation statements)

References 37 publications

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“…Recently, we found that the herbal alkaloid, harmine has potential as anti-inflammatory agents that can suppress TNF-α and NO production [10]. We also found using a customdesigned assay for circadian oscillation in vitro that harmine extends the circadian period [11]. The Amaryllidaceae alkaloid, lycorine (3, 12-didehydro-9, 10-[methylenebis(oxy)]-galanthan-1α, 2β-diol) also suppressed TNF-α and NO production, indicating powerful anti-inflammatory activity [10].…”

Section: Introductionmentioning

confidence: 91%

Lycorine, a Candidate for the Control of Period Length in Mammalian Cells

Onishi

Kawano²,

Yamazaki³

2012

Cell Physiol Biochem

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Plants of the Amaryllidaceae family have been used as therapeutic agents against CNS related maladies such as Alzheimer′s disease. The known primary alkaloid constituents have significant biological activity. We identified the Lycoris alkaloids lycorine and lycoricidinol from Amaryllidaceae using a real-time reporter gene assay system based on NIH3T3 cells. These alkaloids have a wide spectrum of pharmacological actions and dose-dependently lengthen the circadian period. When cells that had been incubated with lycorine or lycoricidinol were washed and then incubated without these alkaloids, period length reverted to that of control cells, suggesting that elongation of the circadian period induced by lycorine and lycoricidinol is reversible. Although one of its major activities is the inhibition of protein synthesis, lycorine induced dose-dependent period elongation regardless of the presence of cycloheximide and moreover, cycloheximide, itself did not affect period length, suggesting that lycorine dose-dependently extends the circadian period by a mechanism other than translational inhibition. Real-time RT-PCR showed that lycorine enhanced RORα and Bmal1 transcription, and exogenous expression and knockdown of Bmal1 also caused long and short periods, respectively, thus confirming the phenotype indicated by lycorine. These data indicate that lycorine and lycoricidinol modulate Bmal1 transcription and the circadian period, and also suggest that Lycoris alkaloids are novel contributors to the control of period length in mammalian cells.

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Section: Introductionmentioning

confidence: 91%

Lycorine, a Candidate for the Control of Period Length in Mammalian Cells

Onishi

Kawano²,

Yamazaki³

2012

Cell Physiol Biochem

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“…15) It is possible that the effect of harmine on the endogenous Bmal1 expression cannot be mimicked by the promoter activity of a minimal region we previously demonstrated.…”

Section: Discussionmentioning

confidence: 99%

“…14) We previously reported that harmine dose-dependently lengthens the circadian period in NIH 3T3 cells. 15) However, several studies have demonstrated that the signals that are input into the circadian clock in the SCN considerably differ from those input into peripheral cells. 1,2,22) Thus, how harmine affects the master clock in the SCN is critical to understand.…”

Section: Discussionmentioning

confidence: 99%

“…[11][12][13] Several psychiatric conditions, including depression, are closely associated with the circadian clock. 14) Although we previously reported that harmine dose-dependently lengthens the circadian period of Bmal1 expression in NIH 3T3 cells, 15) the effects of harmine on the master clock in the SCN remain unknown. We therefore evaluated clock protein dynamics in neuronal cells and in SCN slices by monitoring PER2::LUC bioluminescence in real-time to determine the effects of harmine on the master clock in the SCN.…”

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confidence: 99%

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Harmine Lengthens Circadian Period of the Mammalian Molecular Clock in the Suprachiasmatic Nucleus

Kondoh

Yamamoto

Tomita

et al. 2014

Biological & Pharmaceutical Bulletin

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The circadian clock is a cell-autonomous endogenous system that generates circadian rhythms in the behavior and physiology of most organisms. We previously reported that the harmala alkaloid, harmine, lengthens the circadian period of Bmal1 transcription in NIH 3T3 fibroblasts. Clock protein dynamics were examined using real-time reporter assays of PER2::LUC to determine the effects of harmine on the central Key words carboline alkaloid; circadian clock; PER2::LUC protein; real-time reporter assay; suprachiasmatic nucleus The circadian clock is an endogenous cell-autonomous system that generates circadian rhythms in the behavior and physiology of most organisms. The master clock in mammals is located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus, 1,2) which controls most aspects of physiology such as sleep-wake cycles, body temperature, hormone secretion, blood pressure and metabolism.3,4) The circadian clock mechanism consists of a network of autoregulatory transcription-based feedback loops that drive the rhythmic expression of clock genes such as Per1, Per2 and Bmal1, 5) and these cell-autonomous and self-sustained oscillators are found not only in the SCN but also in peripheral tissues as well as dissociated cells. Acute induction of the mRNA expression of clock genes plays a critical role in phase shifting the circadian clock both in cells cultured in vitro and in vivo. In addition to transcriptional feedback regulations, some essential roles of post-translational modifications such as phosphorylation and ubiquitination have been reported. [6][7][8] The harmala alkaloid, harmine, is a β-carboline alkaloid that was originally isolated from seeds of Peganum harmala and Banisteropsis caapi, both of which have traditionally been used in ritual and medicinal preparations of the Middle East, Central Asia and South America. 9) Harmine is also found in common plant-derived foods and animal tissues, 10) and it has antiplasmodial, antioxidative, antimutagenic and antigenotoxic activities, as well as antidepressant properties.11-13) Several psychiatric conditions, including depression, are closely associated with the circadian clock.14) Although we previously reported that harmine dose-dependently lengthens the circadian period of Bmal1 expression in NIH 3T3 cells, 15) the effects of harmine on the master clock in the SCN remain unknown. We therefore evaluated clock protein dynamics in neuronal cells and in SCN slices by monitoring PER2::LUC bioluminescence in real-time to determine the effects of harmine on the master clock in the SCN.

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“…Harmine is widely distributed in nature, such as in various plants, marine creatures, insects, mammalians, human tissues and body fluids. Harmine have antimicrobial, antiplasmodial, antifungal, antioxidative, antitumor, antimutagenic, cytotoxic and hallucinogenic properties [1][2][3][4][5][6][7] . Beta-carboline compounds act as inverse agonists at the benzodiazepine site of the gammaaminobutyric acid type A receptors and have actions entirely opposite to those of the anxiolytic benzodiazepines.…”

Section: Introductionmentioning

confidence: 99%